Parallel production of high density arrays

ABSTRACT

Internet communication technology is combined with global position systems (GPS) to provide anyone with access to the Internet or web to locate and determine conditions relating to a specific unit or vehicle or fleet of units or vehicles anywhere in the world. The unit or vehicle may communicate directly with the web for location based or location valuable information. Communication between units and/or vehicles is also provided. A transceiver device is located onboard the vehicle/unit and can be accessed by a local Internet interface via common carrier such as cellular telephone or the like. The transceiver includes an integral GPS signal generator and other identifying data. Once the transceiver is accessed by the Internet, the identifying data and the GPS signal are transmitted via the transceiver to the web, where it may be reviewed by any party having authorized access to the web site containing the information. The system provides instant identification of the location of any monitored unit or vehicle anywhere in the world through a local access site. The transceiver may be linked to an onboard processor, which may be a limited, dedicated processor or an expanded general purpose processor, whereby the transceiver can send and receive commands which are processed by the processor to initiate or report certain actions or conditions.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention is a method for producing and/or using arrays whichcontain a multiplicity of compounds for the purpose of screening toidentify molecules with desirable properties. The various compoundsforming the elements of the array can be synthesized in place usingcombinatorial synthesis schemes, or pre-synthesized compounds can beincorporated into the array. Applications to genetic screening, in vitrodiagnostics, and drug discovery are anticipated.

[0003] 2. Discussion of the Prior Art

[0004] Current trends in medical diagnostic testing and pharmaceuticalresearch are toward conducting a large number of tests concurrently on asingle device. For example, one such device has been called a DNA “chip”for sequence analysis. A DNA chip contains a large number (thousands) ofunique DNA molecules (probes) immobilized on a flat surface in the formof an array (e.g. checker board). The company Affymax uses aphoto-lithographic method to produce DNA chips (Fodor, S.P.A., et.al.,Science, 1991, 251, 767-773). Another approach is to use pre-synthesizedmolecules which are applied and immobilized to a suitable substrate(e.g. microporous membrane).

[0005] For example, an unknown sample of DNA (target) is applied to thechip and a hybridization pattern is formed. The pattern is indicative ofthe strength of interaction between the target DNA and the variousimmobilized probes and can yield sequence information. When the sequenceof the target DNA is not known the technology is generally referred toas sequencing by hybridization (SBH) as described in U.S. Pat. No.5,202,231. In other applications where the sequence of the target isknown and detection is directed at identification of a change associatedwith a disease state the method is commonly referred to as“re-sequencing” or allele specific oligonucleotide hybridization.

[0006] Another trend in the arena of pharmaceutical drug discovery isknown as combinatorial synthesis. In this case a large number of similarcompounds are synthesized and simultaneously screened for the desiredbiological response, for example binding to a receptor molecule. Whenone or more candidate compounds in the combinatorial bank are discoveredthey are synthesized in larger quantities for further testing. Moleculesof interest include peptides, nucleic acids as well as drug compoundssynthesized by standard organic chemical methods or other novel methodsfor drug discovery.

[0007] Finally, in the area of in vitro diagnostics there is a need forpanel assays where several tests are run concurrently on a given sampleusing an array of immobilized binding agents. An example of such arrayimmunoassay devices is described in U.S. Pat. Nos. 4,591,570 and4,829,010. Pre-manufactured compounds, such as mono-clonal antibodies,are used to make arrays whose elements have particular bindingproperties for diagnostic analysis. In principle a patient test samplecan be simultaneously analyzed for the presence or absence of severalmolecules, i.e. analytes. Further, the levels of the various analytescan be measured simultaneously by quantitative analysis of the signalsdeveloped at each site of the array. In other applications there is aneed for graphic symbols that can be visually analyzed to determine thepresence or absence of a single analyte in a patient test sample. Forthe present invention, the graphic symbol can be thought of as an arrayof individual elements that are spatially arranged to yield a graphicsymbol as a result of the detection process. In this case, the size ofthe array elements determine the “grain” of the graphic symbol.

[0008] Thus, there is a need for methods to produce and concurrentlytest multiple compounds or binding agents in the form of an array. Anadditional requirement is the need for high density devices (i.e. highspatial density) so that the large numbers of compounds are presented ina package of reasonable size. For example, a device that contains allpossible 8-mer DNA sequences composed of the 4 DNA bases, A (adenine), T(thymine), G (guanine) and C (cytosine) requires 48=65536 differentcompounds. If each element (i.e. a zone of immobilized binding agent)was a square only 1 millimeter (1 mm=0.1 cm) in size, an array of 65536elements would be 10 inches on a side. Clearly, such devices would bedifficult to manipulate and would require relatively large amounts ofthe test sample to be spread evenly over the array surface. A 0.1 mmthick layer of test sample spread on a 10×10 inch area amounts to about6.5 ml (ml=milliliter=6.5×10−3 liter). Since most test samples are ofbiological origin, they are typically very expensive, difficult toprepare and in short supply. Examples of test samples are PCR productsor purified drug receptors which are typically available in microliterquantities-1000 times less than in the above example. In most cases, DNAsynthesis requires the use of expensive components, phosphoramidite DNAsynthesis being a case in point, so surface area of the array is alsoimportant during the manufacturing step.

[0009] Thus, the smaller the size of the array elements involved in thesynthesis the more economical the device will be to produce and use.Several methods exist to create chips with large numbers of differentsequences but often result in devices with large features, largephysical size and, hence, low spatial density. For example, one methoduses disks or channels to produce arrays of probe DNA's using standardDNA synthesis chemistry (see for example, Williams, et.al., NucleicAcids Research 1994, 22, 1365 or Southern et.al., Nucleic AcidsResearch, 1994, 22, 1368 and references therein). The drawback of thismethod is that small feature size is not obtained.

[0010] Another method of making DNA chips is to use pre-synthesizedprobe DNA's and a printing device to allow application of the variouscompounds. The probes are applied to the chip with a pin or a pipette inthe pattern of an array and immobilized by any of a variety oftechniques such as adsorption or covalent linkage. An example of suchDNA arrays is described in Stimpson et.al. Proc. Natl, Acad. Sci. USAVol. 92, pp. 6379-6383, July 1996. Since elements of the array areformed by the application of a DNA solution to the surface of the arraythe process is relatively slow.

[0011] One method to produce high density chips uses photo-lithography(Pease et.al., Proc. Natl, Acad. Sci. USA Vol. 91, pp. 5022, 1994). Onedrawback to this method is that it relies on a new DNA synthesischemistry as opposed to the standard phosphoramidite chemistry used incommercial DNA synthesizers. The technology feeds off the methodsevolved in the electronics industry and therefore has some of the samerequirements, vis, accurate positioning to micron scales, clean roomrequirements and the use of multiple photo-masks to define the arraypattern. Although electronic “chips” (for example an Intel Pentium®microprocessor) are mass produced economically, they are typically tooexpensive to be used as a disposable element, as is needed with a DNAchip.

[0012] Another drawback of such chips is the use of a solid impermeablesupport material like a glass slide or cover slip. As a result, only thevery small amount of material immobilized on the surface of the solidchip is used to capture target molecules. An improvement is describedusing porous silicon or channel glass whereby hybridization reactionsoccur within the three-dimensional volumes of porous silicon dioxide ofchannel array glass rather than two-dimensional surface areas (Beattie,K. L., The 1994 San Diego Conference: The Genetic Revolution).

[0013] Unfortunately, all the array fabrication methods mentioned abovesuffer from a common limitation, i.e., each element of each array is aunique synthesis or an application step. This is true even when arrayelements or entire arrays are simply duplicated or produced “inparallel”, or more accurately, concurrently. Since each element is aunique synthesis or application there is a chance for variation betweencorresponding elements on different arrays or, for that matter,duplicated elements on the same array. When multiple arrays are producedconcurrently it is carried out in a two dimensional fashion, i.e.,arrays are produced next to one another in a two dimensional X-Y plane,where X and Y refer to the two degrees of spatial freedom. In aphoto-lithographic process, increasing the number of chips on a wafer(the substrate on which multiple arrays are produced) results in anincrease in surface area which increases demand on the chemicals used inphoto-chemistry (assuming no change in chip size).

SUMMARY OF THE INVENTION

[0014] The object of the present invention is to extend arrayconstruction into a third dimension, Z, so that each array elementformed by a synthesis or application of a binding agent is used toproduce many arrays. Individual arrays are formed by cutting slabs alongthe Z axis of a bundle assembled from the various array elements.

[0015] The present invention forms elements for the construction of twodimensional (X-Y) arrays by synthesis or applications of binding agentsin a third or Z dimension. The invention is based on the observationthat arrays cut from bundles of porous rods or spiral wound poroussheets behave like membranes composed of said porous materials andconduct flow through the multitude of edges exposed during cutting.Surprisingly, liquid flows substantially through the multiple porous rodor sheets which comprise the array and not through the interveningspaces between the array elements.

[0016] In one embodiment, the elements of the array are formed by theends of rods of porous materials which are compatible with a chemicalsynthesis or compound application step. For application of proteinaceous(e.g. antibodies) or nucleic acid (e.g. derived from a cDNA library)compounds the porous matrix can be selected from any of the materialscurrently used to produce microporous membranes by a phase inversion ora leaching process. Examples of suitable microporous membrane materialsare cellulose, nitrocellulose, polysulfone, nylon, polypropylene orglass. (For a discussion on methods of producing microporous polymermembranes see Synthetic Polymeric Membranes, R. E. Kesting, John Wiley &Sons, 1985, ISBN 0-471-80717-6. For a discussion on methods of producingporous glass materials see Solid Phase Biochemistry, W. E. Scouten Ed.,John Wiley & Sones, 1983, ISBN 0-471-08585-5, Chapter 11, Application ofControlled Pore Glass in Solid Phase Biochemistry by W. Haller). Inparticular, nitrocellulose is preferred for protein components whilenylon is preferred for immobilization of nucleic acid compounds. In eachcase, rods or “threads” of such materials can be formed from processessimilar to those used in producing hollow fiber membranes or flat sheetmembranes. Alternatively, materials that are commonly used for producing“threads” or “yarns” by a spinning process can be utilized to make rods,for example, polyester thread. Each rod is dipped or otherwise exposedto a unique binding agent to allow uniform attachment throughout itslength (Z axis). The attachment procedure may involve simple adsorption,covalent attachment chemistries, multiple washing or adsorption steps orother manipulations to achieve the desired properties of the particulararray element. For a complete discussion on methods of covalentattachment to various solid supports see Pierce Catalog and Handbook,1994. Synthesis steps on the rods elements may involve standard DNAsynthesis chemistries or other synthetic methods of organic chemistry toachieve the desired spectrum of molecules for screening as used in drugdiscovery or gene identification. It is important to note that thebinding agent is introduced to the array element in a batch mode, i.e.,the entire rod is treated uniformly. The array elements can be subjectedto a quality control step before assembly into the bundle used to makethe arrays. When all array elements are available they are formed into arod bundle using radial compression about the Z axis of the bundle. Therods may be organized in the bundle by using a guide, i.e., a plate witha series of holes to direct the rods to a particular point of the array.The bundle can be compressed by pulling it through a cone shaped guide.A sheath is wrapped around the bundle, as in the insulation around abundle of conducting electrical wires, to hold the elements in place.The resulting rod bundle is then sliced into multiple arrays along the Zaxis. Each array consists of a two dimensional arrangement of rodelements with the various compounds displayed on the newly cut ends ofeach rod. Hence, each synthesis or application step to produce a givenarray element is used to produce many arrays. Uniformity of bindingagent is anticipated for a given batch of arrays because any givenelement is produced by a single synthesis or application step. This isopposed to prior art where each element is produce by a uniqueapplication or synthesis, even when said reactions are carried out inparallel. Another interesting feature of the method is that arraydensity is determined by the diameter of the rod elements and is notlimited by the density of the reagent application or synthesis (e.g. inkjet or photo-lithography).

[0017] In some cases it may be desirable to arrange particular rodelements in the form a graphic symbol within the array. To form agraphic symbol from rod elements a guide device would be used to directeach rod element to the correct position in the array to form thegraphic symbol. For a graphic symbol large enough to be read by thehuman eye, multiple rods with the same binding properties are used, Thediameter of the rods at the edge of the symbol determines the grain orpixel density of the final graphic. For a production process, each rodelement is stockpiled on a spool. The spools are dipped or otherwisereacted to introduce the desired immobilized binding agents. The spoolsare fed into the guide and pulled through to form a rod bundle with theappropriate spatial arrangement of rod elements. A sheath is applied tothe rod bundle as it emerges from the guide and the bundle is eitherwrapped on a new larger spool or cut into convenient lengths for storageor directly cut into slab arrays. To create a “plus” symbol, a guidewith the “plus” configuration in the center (i.e. a cruciform hole) with4 surrounding areas in each quadrant formed by the “plus” is used.Multiple Rods from spools treated with the appropriate binding agentsfor a particular assay are fed into the “plus” portion of the guidewhile multiple non-binding rods are fed into the adjacent guides formedby the 4 quadrants. Of course, preformed bundles of rods (i.e. yarns)could be used to feed the quadrant portions of the array. The process issimilar to that described by American Filtrona (Richmond, Va.) and hasbeen given the name “pulltrusion”. In this fashion, arrays with bindingagents or ink printing distributed in various graphic arrangements canbe manufactured.

[0018] In another embodiment, the elements of the array are formed bythe edges of porous sheet materials, such as microporous membranes. Thebinding agents are applied or synthesized on the sheet to create bindingzones of a given binding agent along the entire edge of the sheet.Alternatively, thin lines of compounds are applied or synthesized tocreate multiple array elements on a single sheet of material. In thiscase, each line of immobilized binding agent printed on the sheet isakin to a rod in the aforementioned example. Printing a line of bindingagent on the porous sheet results in migration of the agent into thematrix of the material. When the sheet is cut, the impregnated agent inthe matrix of the sheet is exposed on the freshly cut edge. Themanufactured dimension of the array element is given by the thickness ofthe membrane material and the width of the line used to apply thecompounds. However, depending on the distribution of binding agentwithin the sheet material the actual dimension of the array element maybe smaller, for example, if the binding agent only penetrates {fraction(1/2)}the thickness of the sheet. In some special circumstances it maybe possible to apply or synthesize binding reagents on both sides of asheet to further to further increase array density. After the desiredcompounds are present on the sheets, the sheets are assembled intostacks or rolls before cutting into individual arrays. Individual arraysare generated by cutting slabs as thin as possible along the Z axis ofthe roll or the stack. As in the rod format, each array element isincorporated into multiple arrays. Since one dimension of the arrayelement is determined by the sheet thickness, reasonably high densityarrays can be obtained even with low density reagent applicationmethods.

[0019] An advantage of the printed line format over the rod elementformat is that the spatial arrangement of the array elements (i.e.printed lines) is fixed along the membrane sheet whereas the rods mustbe guided to known positions. An advantage of the rod method over thesheet format is that the manufacturing process for the former iscompatible with a continuous process while the latter is more suitableto a unit process.

[0020] In some cases it may be desirable to use an adhesive compound tobind either the sheets in a stack or the layers of a rolled sheettogether to form a cohesive structure. The adhesive used for thispurpose must not migrate during the cutting process used to form theindividual arrays or else the edges of the sheet material become coveredwith adhesive and are not accessible to test solutions. Suitableadhesives for binding the sheets are heat activated-double sided DowAdhesive Films (Dow Chemical, Midland, Mich.). The important features ofadhesive selection are: (1) the adhesive does not wet and therebyocclude the pores of the sheet material before and during setting (2)the adhesive sets to a substantially solid consistency that does notmigrate and cover the sheet edges during cutting (3) the set adhesive isnot brittle and susceptible to cracking when the individual arrays arereleased from the bundle or roll and (4) the adhesive is stable to theaqueous solvent of the test sample. In general, pressure sensitiveadhesives (e.g. Scotch Tape®, 3M, St. Paul, Minn.) are not desirablebecause of adhesive migration during mechanical cutting. However, othercutting methods using lasers may allow the use of pressure appliedadhesives. One advantage of the roll format over the stack format isthat, typically, the compressional forces supplied by the sheath in therolled structure are sufficient to maintain the integrity of theindividual arrays cut from the roll without using any adhesive. This istrue for both rod bundles and spiral sheet bundles.

[0021] The array is then used to carry out screening tests or diagnosticevaluations. In one procedure, a test sample is exposed to all the arrayelements by application of a small volume of liquid to the top of thearray surface. The liquid is drawn into the array by capillary action.To improve sensitivity, more fluid can be drawn through the array bysetting it on an absorbent pad. A washing step can be incorporated toremove unbound components of the test sample from the array. Arrayelements which have affinity for components of the test sample willretain said components by specific binding events. In a sense, the arrayacts as a membrane which is composed of short segments of the porousmaterials used to make the elements of the array. In another procedure,the array is simply soaked in a test sample and the binding reactionproceeds by diffusion of target molecules to the surface of the array orinto the matrix of the array. A sample contains the component orcomponents whose binding patterns are to be identified by use of thearray. For examples, samples may be derived from PCR amplification ofmaterials collected from a human patient, plant or other organism, theproducts of a combinatorial synthesis, a prospective drug, an antibodyor mixture of antibodies, or a volume of blood, plasma, serum or urine.In each case, those skilled in the art recognize the need for theappropriate sample preparation before applying the sample to an arrayfor binding analysis. For example, filtration, centrifugation, oraddition of agents to prevent non-specific binding are among thepossible operations in preparation of the sample before it is introducedto a diagnostic test.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]FIG. 1A is a schematic view of the rod bundle 10 consisting ofmultiple rod elements 11, each with a biological binding propertiesimparted by immobilization of a suitable binding agent. The bundle isbound and radially compressed about the Z axis with sheath 13. The endsof the rod elements are exposed and regenerated during cutting of thebundle.

[0023]FIG. 1B is an end view of an array cut from bundle 10 showingsheath material 13 and rod ends 12.

[0024]FIG. 1C is a perspective side view of the array cut from bundle10.

[0025]FIG. 2A is schematic view of the sheet material 210 with line ofprinted binding reagents 230 and lines of hydrophobic ink 220 to form areagent impregnated sheet 200.

[0026]FIG. 2B is an enlarged side view of a small portion of sheet 210to reveal details of the reagent zones 230 and hydrophobic ink lines220. Note that the reagents may not extend through the sheet and thedistribution within the sheet is dependent on the printing method.

[0027]FIG. 2C is a schematic view of the process where by the reagentimpregnated sheet 200 is rolled about a cylindrical support 240 to forma spiral wound structure of multiple layers separated by an interstitialspace 250 between said layers.

[0028]FIG. 2D shows an end view of an array cut from the roll of FIG. 2Cafter rolling is complete and the structure is bound with a sheath 260.The array is a spiral structure of multiple layers of sheet material 210separated by interstitial spaces 250 and wrapped about a core cylinder240. Each array cut from the bundle is identical with respect to thearrangement of reagent zones 230.

[0029]FIG. 2E show a side perspective view of the spiral array fixed toan absorbent pad 270 to allow liquid to flow through the top of thearray and out the distal side into the pad.

[0030]FIG. 3A shows a laser printer image of 4 arrays generated by theprocess described in Example 3. The arrays were placed on a scanner andscanned at 600 dpi with 256 gray levels and the data stored as a TIFFfile.

[0031]FIG. 3B shows an enlarged image of a small section from one arrayof FIG. 3A.

[0032]FIG. 4 shows a laser printed image of 2 arrays generated by theprocess described in Example 4. The image files were generated atdescribed in FIG. 3A.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] A particularly useful application of the invention is theproduction of arrays derived from cDNA libraries. For example, a sheetof nylon membrane is treated with sodium hydroxide solution to allowbinding of DNA samples derived from a cDNA library of M13 clones(Drmanac, R., Electrophoresis, 1992, 13, 566-573). Using a suitableprinting method, lines of different DNA samples are applied to themembrane. Reagent jet printing can easily print a line on the sheet orotherwise a pin applicator is used so that multiple dots from the pinoverlap to form a line. The different reagent lines on the sheet areformed as close together as possible and with minimum line width allowedby the printing method so that array density is maximized. Reagent jetprinting is described in U.S. Pat. No. 4,877,745 and can print lineswith a width on the order of 0.001 inch (0.001 inch=0.025 mm=25microns). In some cases it may be desirable to pre-print identificationlines or demarcation lines using insoluble inks when the bindingreagents are dissolved in aqueous solutions. Printing of insoluble inksis commonly used to produce grids on microporous membranes used formicrobiological analysis and said grid patterns must be water insolublefor use in water analysis (see catalog from Millipore, Bedford, Mass.section on microbial analysis). In some cases it may be desirable topre-form hydrophobic lines between zones intended for binding agentapplication. Formation of hydrophobic areas on microporous membranesheets is commonly used to prevent unwanted intrusion of liquids intomembrane edges during testing of bacteriostatic drugs (see catalog fromMillipore, Bedford, Mass. Edge-Hydrophobic Membranes).

[0034] The array elements formed by drawing lines on a sheet can beidentified by several means, viz., (1) spatial arrangement and theuniform size of each element (2) use of ink marks to denote thestart/stop of a reagent zone or (3) use of identification ink marksprinted adjacent to each compound and observed on the edge of the sheet.Ink printed on the surface of porous sheets results in some migration ofthe ink into the matrix of the sheet. When the sheet is cut, the inkwithin the body of the porous material is clearly visible. Physicalmarkings such as holes or notches generated by photo-masks and excimerlasers can also substitute for visible ink marks or paints.

[0035] Reagent jet printing can also be used to generate combinatoriallibraries by chemical synthesis as described in U.S. Pat. No. 5,449,754.For the present invention, the combinatorial method described in U.S.Pat. No. 5,449,754 is used to print lines as opposed to the spotsdescribed therein.

[0036] After reagent application, the membrane is rolled around a rodshaped support to form a tight spiral of membrane material similar to a“jelly roll”. The outer surface is bound with a material that suppliesradial compression (e.g. heat shrink insulation or adhesive tape) andthe resulting roll is cut into individual arrays along the Z axis. Inthis case, the arrays are spiral in nature with each array elementformed by the freshly cut edge of the sheet material impregnated withthe various binding agents. The support rod can be a hollow tube or asolid cylinder. When a pressure sensitive adhesive is used for thesheath, a few layers of untreated sheet are wrapped on the outside ofthe spiral to prevent direct contact between the tape and arrayelements. In this way, the array elements are protected from adhesivemigration during cutting.

[0037] The process is as follows: printing lines that are 0.1 mm wide(0.1 mm=100 microns) on a membrane that is 0.1 mm thick results in asheet of membrane with 65536 binding agents with a length of 655centimeters (i.e. 65536×0.01 centimeters=655 cm=258 inches=21.5 feet).This calculation is consistent with reagent lines that are 100 micronswide and touching one another or reagent lines that are 50 microns wideand delimited on each side by a 50 micron ink line-well within thetechnical capabilities of current jetting techniques. The binding agentsare either synthesized on the solid supports as lines or applied aslines from pre-synthesized materials stored in 384 well microliterplates (170 plates required). When creating such large arrays it may beconvenient to divide the sheet into smaller units for printing, on theorder of 1 foot long each containing 3,048 reagent lines. The individualsheets can be tested for quality before joining into a 21.5 foot sheetfor assembly of the spiral bundle.

[0038] An automated device to apply the multitude of reagents to a 21.5foot sheet is assembled from an X-Y-Z table (e.g. Asymtek) fitted with areagent dispenser, a step motor controlled take up spool and anadjustable drag pay-out spool. The roll of membrane is mounted on thepay-out spool, fed though guides on the X-Y-Z table surface and attachedto the take-up spool. The X-Y-Z table is used to pick up the reagentsfrom the 384 well micro-titer plates using a dispensing device (e.g. an8 tip pipette) and draw lines across the sheet of membrane. The membranecan be pre-printed with the identification/zone isolation lines or thisstep can be carried out upstream of the reagent application. After thereagent lines are drawn, the take-up spool is incremented to advance themembrane sheet and the printing process is repeated using theappropriate sheet advancements. After all reagents are applied thetake-up spool is bound and cut into individual arrays.

[0039] The width of the sheet (Z axis) is determined by the number ofarrays to be generated of a given thickness. The number of arraysobtained from a spiral bundle is given by the sheet width divided by thethickness of the individual arrays. The 655 cm long sheet is rolledaround a 0.5 outer diameter tube (e.g. plastic straw) to form a spiralroll with about 121 turns whose outer diameter is surprisingly onlyabout 3 cm or 1.15 inches. The outer diameter of the spiral bundle canbe calculated by noting the surface area of the bundle and dividing bythe surface area of an individual array element multiplied by the numberof array elements. That is, 65536 elements multiplied by the elementarray (0.01 cm×0.01 cm=0.0001 cm2) gives a total area of 6.6 cm2 whichis equal to the area of a circle 3 cm in diameter (pi r2=6.9 cm2) minusthe area of the 0.5 cm core (pi r2=0.2 cm2). Improvements in spatialdensity of the array are realized by decreasing the membrane thicknessand reducing the width of the reagent lines. Using a membrane that is 10microns thick (10 microns=0.01 mm=0.001 cm) the outer diameter of the21.5 foot spiral wound bundle is only 1 cm with a 0.5 cm core.Alternatively, the printing could be carried out on commerciallyavailable membranes which are 100 microns thick and after printing themembrane thickness reduced to 10 microns by mechanical compression usingrollers. Of course, such a process would substantially reduce the poresize of the membrane and may not permit the use of large labels likecolloidal gold or selenium colloid. The spiral is bound and then cutalong the z-axis (i.e. the membrane sheet width) to create individualarrays with identical zones of immobilized bindings agents. Thinnerarray slabs will yield more arrays from a given bundle. Cutting by handcan easily give arrays 1 mm in thickness so that a 8 inch (20 cm) widesheet yields 200 arrays for each bundle. More sophisticated methods ofcutting (e.g. laser light) could yield arrays of 0.2 mm in thickness andincrease this number to 1000.

[0040] Attachment of pre-synthesized binding agents can be carried outin a variety of ways both by adsorption or by covalent attachment.Nitrocellulose has a natural affinity for proteinaceous materials likeantibodies and the material can be directly applied and immobilized byadsorption. For DNA, a number of commercially available membraneproducts exist for covalent linkage. For example, Immobilon (Millipore),or Biodyne C (Pall Biosupport, Glencove, N.Y.) have been used forcovalent immobilization of small nucleic acids (10-20 bases) via anamino group added during synthesis. Alternatively, large DNA moleculescan be covalently linked to nylon membranes using an ultraviolet lightbox, for example, Strata-linker (Stratagene, La Jolla, Calif.). The mainrequirement of the porous material used for immobilization is that itallow some of the binding agent to penetrate into the matrix, i.e., morethan pure surface deposition. In addition, since the matrix of thematerial forms the binding zones of the array a substantially uniformmembrane is desired. For this reason, membranes with a highly asymmetricstructure or which contain embedded fabrics are less desirable for thepresent invention than uniform membranes.

[0041] Reacting an entire sheet or rod element by dipping into acontainer of chemical solution is a convenient method of producingcompounds by combinatorial synthesis. For example, all possible 4-merDNA sequences would require a “book” of 44=256 sheets or pages. Pagesize is selected to allow convenient handling by hand or machine. Thepages are placed into tubes with the appropriate connections on each endto substitute in place of the standard glass bead columns of acommercially available DNA synthesizer (e.g. Applied Biosystems, FosterCity, Calif.). In the first step, groups of 64 pages are reacted witheach base A, T, G, and C. Next step, 64 page books are made by combining16 pages from each of A, T, G, and C piles. The new books are reactedwith A, T, G, and C to form all possible dimers (16 in all), eachduplicated 16 times. Next step, 4 new 64 page books are made from thedimer pages, i.e., AA, AT, AG, AC, TA, TT, TG, TC, . . . CC. At thisphase, each of the 4 new books are identical and contain 64 pages madeup of the 16 different dimers each duplicated 4 times. The 4 books arereacted with A, T, G, and C to form all 64 possible trimers. The last 4books are assembled from the trimer pages, each book identical and eachtrimer page present only once. The final A, T, G, or C base is added toeach book and all are combined to form the 256 page book of all possible256 sequences of 4-mer DNA with a unique sequence on each page. The bookcould be cut into several books of smaller width/height with each havingall 256 of the 4-mer sequences. Alternatively, the pages of the book canbe held together in a stack using a glue, bonding material, ormechanical device to from a solid stack of pages which are then cut inthe z-axis to create one dimensional arrays formed by the edges of thepages. Alternatively the pages can be rolled into a spiral array typestructure using several pages instead of just one as described above andarrays generated by cutting slabs. The mechanics of combinatorialsynthesis using a flat sheets or rods of material are the same as thosedescribed by U.S. Pat. No. 5,175,209 with the flat sheets or rodelements replacing the porous wafers as the substrates for synthesis.The book format can attain reasonable spatial densities by using thinsheet materials, e.g., track etch polyester or polycarbonate membranesare only 10 microns thick so that 1000 pages combine to give a book only1 cm thick.

[0042] The sheet or rod materials must be compatible with the reagentsused during organic synthesis. Typically glass particles or cross-linkedpolystyrene particles are used in standard DNA synthesis withphosphoramidite chemistry and the solvents acetonitrile,dichloromethane, and tetrahydrofuran are present. Hence, a likelycandidate for the present invention is Empore®, a sheet of chemicallybonded silica particles suspended in a web of polytetrafluoroethylene(PTFE) microfibrils, i.e., both the silica and PTFE are resistant to thechemicals used in DNA synthesis (Empore® is a trademark of 3M, Minnesotaand the material is available from Analytichem International, HarborCity, Calif.). Another possible support is cross-linked polystyrene insheet form instead of micro-particle form. In this case a thin sheet ofpolystyrene would be treated in the same fashion as the microporousstyrene particles to obtain a cross-linked-solvent stable structure.Alternatively, the cross-linked polystyrene beads could be incorporatedinto an Empore type material. Another material that has excellentresistance to organic solvents is microporous PTFE available fromMillipore under the names Fluoropore® and Mitex®. Since these materialdo not have the required functional groups to carry out solid phaseorganic synthesis they would have to be surface modified, for example,by using a procedure described in U.S. Pat. No. 4,794,002. A microporousmembrane with the required solvent resistance and functional groups forsolid phase organic synthesis is hydrophilic Durapore®, also availablefrom Millipore. Surface modified polypropylene membranes are also usedfor solid phase synthesis of oligonucleotides (Matson, et.al.,Analytical Biochemistry 1994, 217, 306-310). Finally, microporous glassin sheet or rod configurations are available from Asahi Glass America,Inc., NY, N.Y. in a wide range of pore sizes from 0.008 micron up to 5micron. While this material would be most suitable for DNA synthesis,clearly, the brittle nature of the porous glass sheet would not becompatible with the spiral bundle and the rod bundle would be required.A final option is to synthesize the binding agents on standard supports,i.e., micoporous glass particles, and immobilize the particles in theporous material by physical trapping/filtration. In this way thematerial does not have to be exposed to the organic solvents used insynthesis.

[0043] Identification of the array elements that generate positive ornegative label reactions is accomplished by noting the positions of rodsor sheet elements. However, in some cases it may be desirable tosynthesize a number of compounds at random. In cases where a very largenumbers of compounds are to be generated, a random or Monte Carlo typeapproach is suitable. For example, if all possible pentipeptides of say,20 different amino acids are to be generated then an array would require205=3,200,000 elements (or probe sites on an array); a difficult andlarge number of elements to screen for binding. In a statisticalapproach we randomly sample 5000 of the possible 3,200,000 combinations.The first 20 bundles would contain 250 rods reacted with each of the 20amino acids and marked accordingly. The rods would then be combined and“shuffled” as in a deck of cards. Shuffling could be carried outmanually or using electronically generated random numbers. The secondset of 20 bundles would be formed by “dealing” out 20 piles from therods of the first synthesis. Each bundle is reacted with one of the 20amino acids and then combined for shuffling and dealing. At the end of 5cycles a random sampling of 5000 peptides from the 3,200,000 possiblepeptides is generated for testing. Any binding motif established by therandom experiment would help to narrow the search and allow for acomplete search of a subset of the 20 amino acids. Of course, thisapproach would find most utility when the number of combinations is evengreater than the example presented here.

[0044] Marking the rods can be accomplished by paints or physical marks.For example, after each step of synthesis, the bundle of rods is dippedin a paint at one end. Spin coating the paint forms a thin zone of paintfor later identification of the synthesis step. Different colors areused to identify the sequence such as red-adenine, blue-guanine,yellow-cytosine and green-thymine in DNA synthesis. At the end ofsynthesis, each rod element is coated with a series of paints thatrepresents the sequence of synthesis steps. The series of bands arerevealed by cutting a rod and examination in a microscope to give thespatial distribution of the elements in all arrays in the bundle. Notethat individual rods must preserve their spatial arrangement throughoutthe Z-length of the bundle. If exposed to the organic chemicals of asynthesis, the paint must be compatible and resistant to the solventsused during synthesis. In most cases of organic synthesis, an epoxy orsilicon based paint that chemically cross-links during curing issuitable provided strong acids or oxidizing agents are avoided. In thisregard, marking by physical damage using laser ablation methods hascertain advantages.

[0045] A large number of formats can be used to detect which elements ofthe array have bound components from the test mixture. If high densityarrays are not needed, the target molecules can be radioactively labeledwith P32 and array binding detected using autoradiography.Unfortunately, the spatial resolution of P32 autoradiography is notsufficient for use with high density arrays with elements on the orderof 10 microns and other methods are needed. Other methods using eitherdirect or indirect labeling with enzymes or flurophores are possible.For a comprehensive discussion on methods of detection and assay formatssuch as sandwich assays or competition assays refer to Pierce Catalogand Handbook 1994. For example, the target molecules of the test samplecan be labeled with biotin or a biotinylated antibody with affinity forthe target molecule can be used for the same purpose. Subsequent bindingof target components to the array elements results in a localizedaccumulation of the biotin moiety. The array elements containing thebiotin label are revealed using standard enzymatic chemistries togenerate colorimetric, fluorigenic, or luminescent based signals. Forexample, avidin labeled alkaline phosphatase will bind to biotin and avisible dark blue signal generated by the action of alkaline phosphataseon BCIP+NBT (5-bromo-4-chloro3-indolyl phosphate and nitro bluetetrazolium). Other enzyme-substrate combinations can be used togenerate fluorescent and luminescent signals. Alternatively, avidin,streptavidin, or antibodies which bind biotin can be directly labeledwith a fluorphore (e.g. fluorescein) or a microparticle dye (e.g. goldcolloid or selenium colloid as in U.S. Pat. No. 5,120,643) and exposedto the array to develop a signal. Another option is to use labeledsecondary antibodies which directly bind to the target molecule to carryout detection as in a sandwich assay format. In cases where flow throughthe array is needed to improve sensitivity, the porous rod or sheetmaterials must have a pore size sufficiently large to allow entry of thelabel into the matrix, otherwise the label reaction is confined to therod surface. Flow through the array is especially desirable whencolloidal labels are used to generate the signal.

[0046] Cutting the rod or spiral bundles to form the arrays can beaccomplished using mechanical or laser methods. Razors or knife bladescan be used to manually cut porous polymeric materials to give arrays0.2-1 mm thick. A microtome device is able to cut thin sections ofvarious materials for microscopic evaluation and may be useful for arraygeneration. The samples used in such a device are usually biological innature and derived from tissue samples, for example, a tumor surgicallyremoved from a patient. Typically, the sample preparation for cuttingthin sections with a microtome makes use of paraffins or plasticembedding media. The thin section is then “stained” using the specificinteractions generated by antibody binding followed by staining withantibody coated collodial gold, or followed by staining with antibodycoated collodial gold, or “Immunogold” (Ted Palla, Inc. Redding, Calif.)or the variety of enzyme/substrate combinations described above thatgenerate fluorescent or visible colors that can be observed with asuitable microscope. In the present invention, the rod or spiral arrayscould be subject to the same manipulations when flow through the arrayis not required for signal development. Within this context, the arraybecomes analogous to the tissue sample with the various elements of thearray available for binding with antibodies or nucleic acids or otherspecific interactions known to those skilled in the art. To summarize:prior art in the area of microscopy support the concept that the arrayscan be cut very thin using mechanical means and that the array elementsare able to bind biological agents even when that are embedded in aparaffin or plastic compound that helps to support the specimen duringmechanical cutting.

[0047] Both the rod bundle and spiral bundle arrays are surprisingstable to handling. In the case of rod bundles formed from glass orceramic materials a fine abrasive diamond or carborundum blade isapplicable to cut arrays. It may be possible to use more sophisticatedcutting methods using CO2 or excimer lasers provided the compounds onthe cut edge are not damaged by heat generated during the process. CO2lasers are frequently used in the clothing industry to cut multiplelayers of cloth or synthetic fabrics without damage from heating.Excimer lasers are used in eye surgery and since the process isphoto-ablation, there is little damage to the surrounding tissue. Bothmethods may prove useful in cutting arrays from the spiral or rodbundles.

[0048] In summary, the invention is directed toward the detection ofcomponents in a sample mixture or detection of compounds on an array by:

[0049] a) immobilizing binding compounds onto rod shaped array elements;

[0050] b) forming a bundle of the rod elements using a guide to create aspatially uniform arrangement of rod elements and securing with a sheathmaterial;

[0051] c) cutting individual arrays from the bundle to generate amultiplicity of binding surfaces and fixing or placing one side of thearray to an absorbent pad;

[0052] d) applying a sample to the surface of an array and allowing thesample to flow through the porous rod elements of the array into theabsorbent pad;

[0053] e) applying a washing solution to remove unbound compounds of thesample mixture;

[0054] f) applying a labeled compound that binds to the components ofthe sample mixture which are bound to elements of the array;

[0055] g) washing away unbound label and observe binding patterndirectly or by application of a reagent to allow detection of the boundlabel.

[0056] h) correlating the binding pattern of the binding surfaces withthe composition of elements in the array.

[0057] The invention is directed toward the detection of components in asample mixture or detection of compounds on an array by:

[0058] a) forming lines of immobilized binding compounds on a sheet ofmaterial, wherein lines of binding compounds maybe separated byidentification marks, and the binding material is impregnated into thethickness of the sheet material;

[0059] b) rolling the printed sheet into spiral wound structure about arod and securing roll with a sheath;

[0060] c) cutting individual arrays from the bundle to expose bindingelements formed by the freshly exposed edge of sheet material separatedby identification marks and interstitial space between adjacent membranelayers, and fixing or placing one side of the array onto an absorbentpad;

[0061] d) exposing and develop the array as in e-h above;

[0062] e) correlating the binding pattern on the array with thecomposition of the binding elements.

[0063] The invention is directed toward the detection of components in asample mixture or detection of compounds on an array by:

[0064] a) synthesizing of binding compounds onto rod shaped arrayelements using a randomized method;

[0065] b) marking the identification of each rod at each synthesis stepby spin coating with paint;

[0066] c) forming a bundle of the rod elements and securing with asheath material;

[0067] d) exposing and developing the array as in e-h above;

[0068] e) correlating the binding events with the identification marks.

[0069] The invention is directed toward the detection of components in asample mixture or detection of compounds on an array by:

[0070] a) immobilizing binding compounds onto rod shaped array elements;

[0071] b) forming a bundle of the rod elements and securing with asheath material so that rod elements treated with given binding agentare grouped to create a graphic symbol/s surrounded by rod elements withdifferent or substantially no affinity for components in the testsample;

[0072] c) cutting individual arrays from the bundle and fixing orplacing one side of the array to an absorbent pad;

[0073] d) applying a mixture of sample and label to the surface of anarray, allowing the mixture to flow through the porous rod elements ofthe array into the absorbent pad and form attachments between the label,analyte and immobilized binding agent as in a “sandwich assay” format;

[0074] e) washing away unbound label and observe binding patterndirectly or by application of a reagent to allow detection of the boundlabel;

[0075] f) correlating the graphic symbol/s with the presence or absenceof analyte(s).

EXAMPLE 1

[0076] A bundle of rods (spun polyester sewing thread, Lily, USA) sometreated with the protein bovine serum albumin (BSA) and some not treatedwere gathered into a bundle and placed into heat shrink tubing andradially compressed. The BSA treatment consisted of soaking the rod in asolution of about 1 mg/ml BSA for 5 minutes, washing with distilledwater for 5 minutes and air drying. Polyester rods treated in thisfashion adsorb BSA throughout the porous matrix. The resulting bundlewas cut into slabs about 1 mm in thickness to form arrays. Each arraycontains a section from all the rod elements. A solution of seleniumcolloid, a microparticle that binds to bovine serum albumin, was placedon top of the array of porous rods. A piece of absorbent paper wasplaced under the slab to draw the liquid through the array. After liquidwas drawn through, the protein coated rods were clearly visible by a redcolor. The array of porous rods acts like a membrane of porous materialbut consists of a myriad of different zones each of which can havedifferent binding properties.

EXAMPLE 2

[0077] Identification marks on individual rods were produced by spincoating. Rods of porous polypropylene were dipped into acrylic paint,fixed at the opposite end to a motor shaft with tape, and spun atapproximately 1000 RPM to remove excess paint. The process was repeatedusing different color paints to identify a given DNA base in the processof synthesis. The paints were allowed to dry 1 minute betweenapplications while spinning. After the last paint application a bundleof rods was formed and cut to reveal the layers of paint on each rod.Using a 10× stereo microscope it was possible to read the colors of thedifferent layers of paint exposed by cutting the bundle and therebyidentify the sequence of reaction steps for each rod.

EXAMPLE 3

[0078] Reagent demarcation lines were printed onto a sheet of 5 micronnitrocellulose membrane about 6 inches long and 3 inches wide using anStyle Writer II (Apple Computer, Cupertino, Calif.) thermal ink jetprinter. The ink lines were about 1 mm wide and separated by about 2 mmspacing. After printing, the sheet was rolled tightly by hand around aplastic straw, and bound with adhesive tape. The spiral bundle wasplaced inside a metal tube whose inner diameter was slightly larger thanthe outer diameter of the bundle, The a 1-2 mm length of the bundle wasallowed to extend from the end of the metal tube and an array slab wascut with a razor blade using the metal tube as a guide to obtain auniform straight cut. FIG. 3 shows a laser print of the 256 gray levelimage of the array obtained by placing the array on an Epson ES-600Cscanner. Each array has in inner diameter of 0.6 cm, an outer diameterof 0.9 cm and contains approximately 160 array elements, i.e., spacesbetween the ink marks. Microscopic examination showed the ink penetratedabout ½ to {fraction (3/4 )} through the 0.1 mm thickness of themembrane. As a result, each array element defined by the space betweeneach pair of printed lines was clearly visible under a microscope. Thearrays were surprisingly stable and easily handled even though thelayers of the spiral are only held in place by compression between thecentral rod (straw) and the outer sheath (adhesive tape). Arrays as thinas 0.2 mm were cut by hand, albeit, not uniformly. The reagents would beapplied to the spaces between the lines. Since the standard ink for thisprinter is water soluble, reagents would have to be applied in anon-aqueous solvent that does not dissolve this ink or affect themembrane.

EXAMPLE 4

[0079] Lines of BSA were printed by hand on 0.1 mm thick 5 micron porenitrocellulose membranes using a reagent pen device and a ruler. Thelines were about 0.5 mm wide and placed at random spacing along the 6inch length of the membrane. The resulting sheet was rolled, bound andcut as in Example 3. The arrays were placed on a pad of adsorbentmaterial (i.e. a paper towel) and a solution of selenium colloid appliedto the top of the array. The colloid solution formed an annular shapeddrop on the array surface and was adsorbed by the spiral membrane of thearray. Once the array was saturated, colloid solution began to flow intothe underlaying absorbent pad. When excess liquid on top of the arraywas depleted, flow stopped. Flow of colloid solution could be re-startedby applying more solution to the top of the array. In this way, about0.5 ml of colloid solution was drawn through the array. The arrayelements formed by the lines of BSA were clearly visible as dark redbars with dimensions of 0.5 mm×0.1 mm, at various locations throughoutthe spiral array. Visibility of the BSA zones could be enhanced bywashing the array by applying distilled water and letting it drawthrough the array until the background red color was gone. FIG. 4 showsa laser printer figure of the 256 gray level image of the array obtainedby placing the array on a scanner.

EXAMPLE 5

[0080] Procedures described in this example are taken from Zhang,et.al., Nucleic Acids Research, Vol. 19, No. 14,3929-3933. Probes thatrecognize normal and mutation sequences of the cystic fibrosis (CF) geneare synthesized with “aminolinkers”. The probes are 21 bases in lengthwith a primary amino group on the 5′ end. As many as 300 mutations areknown for the CF gene so an array may contain 600 such probes with ½representing the normal sequence and ½ representing the mutationsequence. Biodyne C membranes (Pall Biosupport, N.J.) are rinsed with0.1 N HCl then treated with freshly prepared 20%(1-Ethyl-3-(Dimethylamino propyl) Carbodiimide hydrochloride) indeionized water and rinsed with deionized water. The probes are appliedto the Biodyne C membrane as prescribed in a Bio-dot apparatus (Bio-Rad,Calif.) with the exception that the apparatus is modified to form linesinstead of spots. The amino-modified oligonucleoties are applied to theactivated membrane in 0.5 M sodium bicarbonate buffer pH 8.4 for 15minutes. The lines are rinsed with tris buffered saline and 0.1% Tween(Sigma, Mo.). Remaining active groups are quenched with 0.1 N NaOH for10 minutes. The filters are rinsed with deionized water and air dried.Membranes are then rolled about a plastic support 0.5 cm in diameter toform a spiral bundle, bound and sliced into arrays. Detection of CFmutations is performed on biotinylated PCR product from patient samples.The PCR products are denatured with 0.25 N NaOH and hybridized to thearrays in 5×SSPE with 0.5% sodium dodecyl sulfate (1×SSPE=180 mM NaCl,10 mM NaH2PO4, 1 mM ethylene diamine tetraacetic acid, pH 7.2). Sampleis applied to the top of the array and allowed to flow through the arrayinto an underlaying absorbent pad for 30 minutes at 45° C. The requiredincubation times can be obtained by adjusting the pore size of theabsorbent pad, using small amounts of pad, or using intermittent contactwith the absorbent pad. The arrays are washed with 2×SSPE, 0.1% SDS at45° C. for 15 minutes to remove unbound target. Streptavidin-horseradish peroxidase (5 mg/ml, Cetus) in 2×SSPE and 0.1% SDS is drawnthrough the array for 15 minutes and then washed with the same bufferfor 10 minutes. A luminescent signal is generated by flowing a mixtureof equal volumes of ECL Gene Detection reagents A+B (Amersham, Ill.)through the array for 1 minute and applying the arrays to Hyperfilm-ECL(Amersham, Ill.) for a few seconds or minutes.

[0081] The signal appears as a dark spot on the film and the arraypattern indicative of the genetic composition of the patient sample.

EXAMPLE 6

[0082] Lines of biotinylated BSA solution (2.5 mg/ml) were drawn on 5micron nitrocellulose membrane using a reagent pen device. The finestlines obtained by this method were 100 microns in width. The membranewas rolled, bound and cut into slab arrays and placed on a paper towel.A solution of 1% casein and a 1:10,000 dilution of alkalinephosphatase-avidin conjugate (ExtrAvidin®, Sigma Chemical, St. Louis) in20 mM Tris, pH 7.5 was applied to the top of the array and allowed toflow through. The array was then soaked in BCIP/NBT (Sigma FastTM5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium) for 10minutes. Dark purple zones formed at the array rites where biotinylatedBSA was applied.

[0083] While certain features and embodiments of the invention have beenshown and described in detail herein, it will be understood that theinvention encompasses all modifications and enhancements within thescope and spirit of the following claims.

What is claimed is:
 1. A method for the detection of components in asample mixture or detection of components on an array comprising thesteps of: a. immobilizing binding compounds onto a carrier; b. forming abundle of compounds in a generally elongated form by collecting theimmobilized compounds about a common axis to form a bundle; and c.cutting individual arrays from the bundle to generate a spatiallyuniform arrangement of compound samples and carrier.
 2. The method ofclaim 1, wherein the immobilizing step comprises immobilization ofbinding compounds onto rod shaped elements and wherein after the rodsare formed in a bundle, there is included the step of placing a sheatharound the bundle to secure the rods.
 3. The method of claim 2, whereinsaid sheath is an adhesive layer.
 4. The method of claim 2, wherein saidsheath is a heat shrink material applied in circumscribing relationshiparound the bundle and heated to shrink fit.
 5. The method of claim 1,wherein the immobilizing step comprises forming lines of immobolizedbinding compounds on a sheet of material and the bundle is formed by thestep of wrapping the sheet material in a spiral.
 6. The method of claim5, wherein wrapping step includes rolling the sheet about a rod.
 7. Themethod claim 1, wherein the immobilizing step comprises synthesis ofbinding compounds onto rod shaped elements using a randomized method andthe sub-step of marking the identification of each rod at each synthesisstep.
 8. The method of claim 2, wherein sub-step of marking is by spincoating with paint.
 9. The method of claim 1, wherein the forming stepincludes grouping rod elements treated with a given binding agent forcreating a graphic symbol(s) surrounded by rod elements with differentaffinity for the components in the test sample.
 10. The method of claim1, wherein the elongated bundle is formed by stacking flat componentsalong a common axis.
 11. The method of claim 1, the immobilizing stepcomprising forming lines of immobilized binding compounds on sheets ofcarrier material wherein the bundle is formed by alternating layers ofcarrier sheets and adhesive bonding layers.
 12. The method of claim 11,wherein the bundle is spiral wound.
 13. The method of claim 11, whereinthe bundle is a static sheet structure.
 14. The method of claim 1,further including the steps of: a. applying a sample to the surface ofthe array; b. applying a washing solution to remove unbound compounds ofthe sample mixture; c. applying a labeled compound that binds to thecomponents of the sample mixture which are bound to elements of thearray; d. washing unbound label compound; e. observing the bindingpattern; and f. correlating the binding pattern of the binding surfaceswith the composition of the elements in the array.
 15. The method ofclaim 1, further including the step of: a. cutting individual arraysfrom the bundle to generate a multiplicity of binding surfaces andplacing one side of the array to a pad.
 16. The method of claim 15,further including the steps of: a. applying a sample to the surface ofan array and allowing the sample to flow through the array into the pad;b. applying a washing solution to remove unbound compounds of the samplemixture; c. applying a labeled compound that binds to the components ofthe sample mixture which are bound to elements of the array; d. washingunbound label compound; e. observing the binding pattern; f. correlatingthe binding pattern of the binding surfaces with the composition ofelements in the array.
 17. The method of claim 16, wherein the observingstep includes applying a reagent to allow detection of the bound label.18. The method of claim 5, further including the step of separatinglines of binding compounds by identification marks wherein the bindingpattern on the array may be correlated with the composition of thebinding elements.
 19. The method of claim 5, wherein the bindingmaterial is impregnated into the thickness of the sheet material. 20.The method of claim 18, wherein the cutting step comprises cuttingindividual arrays from the bundle to expose binding elements formed bythe freshly exposed edge of sheet material and separated byidentification marks and interstitial space between adjacent membranelayers.
 21. The method of claim 20, further including the step ofplacing one side of the array onto a pad.
 22. The method of claim 21,wherein said pad is absorbent.
 23. The method of claim 22, furthercomprising the steps of: a. cutting individual arrays from the bundle togenerate a multiplicity of binding surfaces and placing one side of thearray to a pad.
 24. The method of claim 23, further including the stepsof: a. applying a sample to the surface of an array and allowing thesample to flow through the array into the pad; b. applying a washingsolution to remove unbound compounds of the sample mixture; c. applyinga labeled compound that binds to the components of the sample mixturewhich are bound to elements of the array; d. washing unbound labelcompound; e. observing the binding pattern; f. correlating the bindingpattern of the binding surfaces with the composition of elements in thearray.
 25. The method of claim 9, further comprising the steps of: a.cutting individual arrays from the bundle and placing one side of thearray to a pad; b. applying a mixture of sample and label to the surfaceof the array, allowing the mixture to flow through the rod elements ofthe array into the pad for forming attachments between the label,analyte and immobilized binding agent as in a sandwich assay format; c.washing away unbound label; d. observing the binding pattern; e.correlating the graphic symbol(s) with the presence or absence ofanalyte(s).
 26. The method of claim 25, wherein the observing stepincludes applying a reagent to allow detection of the bound label.
 27. Amethod for detection of compounds on an array by: a. immobilizingbinding compounds onto rod shaped array elements; b. forming a bundle ofthe rod elements using a guide to create a spatially uniform arrangementof rod elements and securing with a sheath material; c. cuttingindividual arrays from the bundle to generate a multiplicity of bindingsurfaces and fixing or placing one side of the array to an absorbentpad; d. applying a sample to the surface of an array and allowing thesample to flow through the porous rod elements of the array into theabsorbent pad; e. exposing and developing the array; f. correlating thebinding pattern of the binding surfaces with the composition of elementsin the array.
 28. A method of detecting components in a sample mixtureor detection of compounds on an array by: a. forming lines ofimmobilized binding compounds on a sheet of material, wherein lines ofbinding compounds maybe separated by identification marks, and thebinding material is impregnated into the thickness of the sheetmaterial; b. rolling the printed sheet into spiral wound structure abouta rod and securing roll with a sheath; c. cutting individual arrays fromthe bundle to expose binding elements formed by the freshly exposed edgeof sheet material separated by identification marks and interstitialspace between adjacent membrane layers, and fixing or placing one sideof the array onto an absorbent pad; d. exposing and develop the array;e. correlating the binding pattern on the array with the composition ofthe binding elements.
 29. A method of detecting components in a samplemixture or detection of compounds on an array by: a. synthesizing ofbinding compounds onto rod shaped array elements using a randomizedmethod; b. marking the identification of each rod at each synthesis stepby spin coating with paint; c. forming a bundle of the rod elements andsecuring with a sheath material; d. exposing and developing the array;e. correlating the binding events with the identification marks.
 30. Themethod of claim 27, 28 or 29, wherein the exposing and developing stepincludes the sub-steps of: a. applying a washing solution to removeunbound compounds of the sample mixture; b. applying a labeled compoundthat binds to the components of the sample mixture which are bound toelements of the array; c. washing away unbound label and observe bindingpattern directly or by application of a reagent to allow detection ofthe bound label.
 31. A method of detecting components in a samplemixture or detection of compounds on an array by: a. immobilizingbinding compounds onto rod shaped array elements; b. forming a bundle ofthe rod elements and securing with a sheath material so that rodelements treated with a given binding agent are grouped to create agraphic symbol/s surrounded by rod elements with different orsubstantially no affinity for components in the test sample; c. cuttingindividual arrays from the bundle and fixing or placing one side of thearray to an absorbent pad; d. exposing and developing the array, e.correlating the graphic symbol/s with the presence or absence ofanalyte(s).
 32. The method of claim 31, wherein the exposing anddeveloping step comprises the sub-steps of: a. applying a mixture ofsample and label to the surface of an array, allowing the mixture toflow through the porous rod elements of the array into the absorbent padand form attachments between the label, analyte and immobilized bindingagent as in a “sandwich assay” format; b. washing away unbound label andobserve binding pattern directly or by application of a reagent to allowdetection of the bound label.